WO2016091997A1 - Procédé de fabrication d'idalopirdine - Google Patents
Procédé de fabrication d'idalopirdine Download PDFInfo
- Publication number
- WO2016091997A1 WO2016091997A1 PCT/EP2015/079209 EP2015079209W WO2016091997A1 WO 2016091997 A1 WO2016091997 A1 WO 2016091997A1 EP 2015079209 W EP2015079209 W EP 2015079209W WO 2016091997 A1 WO2016091997 A1 WO 2016091997A1
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- WO
- WIPO (PCT)
- Prior art keywords
- compound
- mixture
- fluoro
- solvent
- catalyst
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 44
- YBAWYTYNMZWMMJ-UHFFFAOYSA-N 2-(6-fluoro-1h-indol-3-yl)-n-[[3-(2,2,3,3-tetrafluoropropoxy)phenyl]methyl]ethanamine Chemical compound FC(F)C(F)(F)COC1=CC=CC(CNCCC=2C3=CC=C(F)C=C3NC=2)=C1 YBAWYTYNMZWMMJ-UHFFFAOYSA-N 0.000 title abstract description 6
- 229950005109 idalopirdine Drugs 0.000 title abstract description 4
- 238000004519 manufacturing process Methods 0.000 title description 6
- 238000002360 preparation method Methods 0.000 claims abstract description 14
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- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 44
- 239000000203 mixture Substances 0.000 claims description 40
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 32
- 239000003054 catalyst Substances 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N Vilsmeier-Haack reagent Natural products CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 20
- 229960004592 isopropanol Drugs 0.000 claims description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 16
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 12
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- 238000005984 hydrogenation reaction Methods 0.000 claims description 11
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 10
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- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical group COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 claims description 4
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine group Chemical group NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 4
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- 239000001358 L(+)-tartaric acid Substances 0.000 description 5
- 235000011002 L(+)-tartaric acid Nutrition 0.000 description 5
- FEWJPZIEWOKRBE-LWMBPPNESA-N L-(+)-Tartaric acid Natural products OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 5
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- BQTOKMYKZPCPRW-UHFFFAOYSA-N 2-(6-fluoro-1h-indol-3-yl)ethanamine Chemical compound FC1=CC=C2C(CCN)=CNC2=C1 BQTOKMYKZPCPRW-UHFFFAOYSA-N 0.000 description 4
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- ZZXDRXVIRVJQBT-UHFFFAOYSA-M Xylenesulfonate Chemical compound CC1=CC=CC(S([O-])(=O)=O)=C1C ZZXDRXVIRVJQBT-UHFFFAOYSA-M 0.000 description 1
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 235000012501 ammonium carbonate Nutrition 0.000 description 1
- DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 159000000032 aromatic acids Chemical class 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- JOYKCMAPFCSKNO-UHFFFAOYSA-N chloro benzenesulfonate Chemical compound ClOS(=O)(=O)C1=CC=CC=C1 JOYKCMAPFCSKNO-UHFFFAOYSA-N 0.000 description 1
- KVSASDOGYIBWTA-UHFFFAOYSA-N chloro benzoate Chemical compound ClOC(=O)C1=CC=CC=C1 KVSASDOGYIBWTA-UHFFFAOYSA-N 0.000 description 1
- 229940114081 cinnamate Drugs 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 150000004696 coordination complex Chemical class 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-M decanoate Chemical compound CCCCCCCCCC([O-])=O GHVNFZFCNZKVNT-UHFFFAOYSA-M 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 239000002815 homogeneous catalyst Substances 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- TWBYWOBDOCUKOW-UHFFFAOYSA-M isonicotinate Chemical compound [O-]C(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-M 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000005394 methallyl group Chemical group 0.000 description 1
- RPNNPZHFJPXFQS-UHFFFAOYSA-N methane;rhodium Chemical compound C.[Rh] RPNNPZHFJPXFQS-UHFFFAOYSA-N 0.000 description 1
- IZYBEMGNIUSSAX-UHFFFAOYSA-N methyl benzenecarboperoxoate Chemical compound COOC(=O)C1=CC=CC=C1 IZYBEMGNIUSSAX-UHFFFAOYSA-N 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 239000003658 microfiber Substances 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 229910000480 nickel oxide Inorganic materials 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- GNRSAWUEBMWBQH-UHFFFAOYSA-N oxonickel Chemical class [Ni]=O GNRSAWUEBMWBQH-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 229950009215 phenylbutanoic acid Drugs 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- YAYGSLOSTXKUBW-UHFFFAOYSA-N ruthenium(2+) Chemical compound [Ru+2] YAYGSLOSTXKUBW-UHFFFAOYSA-N 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 239000003751 serotonin 6 antagonist Substances 0.000 description 1
- 229910052814 silicon oxide Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000007070 tosylation reaction Methods 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- APJYDQYYACXCRM-UHFFFAOYSA-N tryptamine Chemical compound C1=CC=C2C(CCN)=CNC2=C1 APJYDQYYACXCRM-UHFFFAOYSA-N 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D209/16—Tryptamines
Definitions
- the present invention relates to the preparation of N-(2-(6-fluoro-lH-indol-3-yl)-ethyl)- 3-(2,2,3,3-tetrafluoropropoxy)-benzylamine, INN-name idalopirdine, and pharmaceutically acceptable salts thereof.
- N-(2-(6-fiuoro-lH-indol-3-yl)-ethyl)-3-(2,2,3,3-tetrafluoropropoxy)-benzylamine is a potent and selective 5-HT 6 receptor antagonist which is currently in clinical development. Its chemical structure is depicted below as Com ound (I).
- This method of manufacture comprises the steps
- WO2011/076212 further discloses 2-(6-fluoro-lH-indol-3-yl)ethylamine hydrogen L-(+)-tartrate (the 1 :1 salt of 2-(6-fluoro-lH-indol-3-yl)ethylamine and L-(+)-tartaric acid) as well as a process for the purification of 2-(6-fluoro-lH-indol-3-yl)ethylamine comprising the steps of:
- DMF N,N-dimethylformamide
- MeOH is methanol.
- THF is tetrahydrofuran.
- TCE 2,2,2-trichloroethanol
- i-PrOH is 2-propanol (isopropyl alcohol).
- RaNi'VRaney nickel is an activated nickel catalyst which is optionally doped with another metal and that comes in different particle sizes and forms
- Cyanide source is KCN, NaCN, or other agents which release the CN “ anion.
- DI is distilled or ultra-pure.
- M is molar
- v/v volume per volume
- HPLC high pressure liquid chromatography
- LC-MS liquid chromatography-mass spectrometry
- Pd/C is palladium on charcoal.
- Platinum/C is platinum on charcoal.
- Rh/C is rhodium on charcoal.
- Pore/Alumina is rhodium on aluminium oxide.
- Ni/Silica-alumina is nickel on a mixture of silicon oxide and aluminium oxide
- PRICATTM is the trademark for a series of supported nickel catalysts on silica with/without added promotors, from Johnson Matthey Process Technologies.
- NMP N-methylpyrrolidinone.
- DMF-DMA N,N-dimethylformamide dimethyl acetal.
- EDG is ethylene glycol
- nickel catalyst refers to catalysts comprising nickel or nickel oxides or mixtures thereof.
- embodiment of the invention is disclosed a process for the preparation of Compound (IV)
- the nickel catalyst is supported on silica or alumina.
- the supported nickel catalyst is selected from the group comprising PRICAT 55/5P and PRICAT 62/15P.
- the alcoholic solvent is methanol, ethanol or 2-propanol.
- the hydrogenation is run at a pressure from approx. 2 to approx. 10 bar, more particularly from approx. 2 to approx. 6 bar and most particularly from approx. 2 to approx. 4 bar.
- the hydrogenation is run at a temperature from about 40 °C to about 70 °C, more particularly from about 50 °C to about 60 °C.
- the hydro genation is run with a loading from about 8 % to about 31 % (w/w) supported nickel catalyst relative to (6-fluoro- lH-indol-3-yl)acetonitrile.
- sodium borohydride is used as the reducing agent for the reduction to Compound I.
- Compound (XIII) is reacted in DMF or NMP as solvent. In a more particular embodiment Compound (XIII) is converted to Compound (XI) using DMF- DMA.
- Compound (XI) is reduced to Compound (X) using Raney nickel or palladium on charcoal as catalyst. In a more particular Compound (XI) is reduced to Compound (X) using hydrazine or hydrogen as reductant.
- Compound (I) forms pharmaceutically acceptable acid addition salts with a wide variety of organic and inorganic acids and include the physiologically acceptable salts which are often used in pharmaceutical chemistry. Such salts are also part of this invention. Such salts include the pharmaceutically acceptable salts listed in Berge, S. M.et al., J. Pharm. Sci. 1977, 66, 1-19 which are known to the skilled artisan. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydriodic, nitric, sulfuric, phosphoric, hypophosphoric, metaphosphoric, pyrophosphoric, and the like.
- Salts derived from organic acids such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used.
- Such pharmaceutically acceptable salts thus include chloride, bromide, iodide, nitrate, acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, isobutyrate, phenylbutyrate, a-hydroxybutyrate, butyne-l ,4-dicarboxylate, hexyne-1 , 4-dicarboxylate, caprate, caprylate, cinnamate, citrate, formate, fumarate, glycollate, heptarioate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, oxalate, phthalate, teraphthalate, propiolate, propionate, phen
- the mixture from reactor A (DEM, water, formic acid, formaldehyde and ethanol at about 20 °C) was added drop-wise to reactor B while keeping the temperature at 2-8 °C.
- the reaction mixture was stirred for additional 10 min at 2-8 °C.
- the reaction mixture was slowly warmed to approx. 40 °C over a 1 h period.
- the reaction mixture was stirred at approx. 40 °C for an additional 1 h.
- the reaction mixture was cooled to about 20°C.
- a 250 L reactor was charged with approx. 40% aq. dimethylamine (35.7 kg, 317 mol) at approx. 17 °C under an inert atmosphere.
- the mixture was cooled to approx. 4.5 °C and glacial acetic acid (43.4 kg, 723 mol) was added dropwise over 140 min while maintaining the temperature at approx. 15°C.
- 37% aqueous formaldehyde 25.9 kg, 319 mol
- reaction was exothermic and reached a final temperature of approx. 40 °C, and it was then cooled down to approx. 20°C.
- the reaction solution was slowly added to a 650 L reactor previously charged with aq. NaOH (3 M) over a period of approx. 40 min.
- the formed suspension was stirred for approx. 40 min while keeping the temperature between 5 to 20 °C.
- the precipitate was filtered from solution, washed with water on the filter, and dried at approx. 50°C to afford Compound (II) (45.4 kg, 81%).
- the mixture was hydrogenated at 4 bar and at the specified temperature for the specified time.
- the reaction mixture was analysed directly by LC-MS.
- DPPF l, -Bis(diphenylphosphino)ferrocene, cas number: 12150-46-8.
- Tris(triphenylphosphine)ruthenium(II) dichloride cas number 15529-49-4.
- Tris(triphenylphosprtine)rhodiutri(I) carbonyl hydride cas number 17185-29-4.
- Example 7 Screening of rhodium, platinum and nickel catalysts
- PRICAT type 55/5P catalyst (14.0 kg) was charged to a reactor followed by charging of a solution of Compound (III) (46.3 kg, 266 mol) in isopropanol (76.4 kg). Then isopropanol (106 L) and aq. ammonia (302 L, 25%) was charged. The mixture was transferred to a steel autoclave under nitrogen, using extra isopropanol (92 L) for washing of reactor. The autoclave was evacuated and then pressurized with hydrogen gas to 3 bar. The content was heated to 55 °C and hydrogenated at 3 bar hydrogen for 48 h. The content was cooled to 25 °C, and the autoclave was purged with nitrogen gas, and the content filtered on a pressure nutsch filter. The filter was washed with isopropanol (2 x 145 L). This yielded a solution of Compound (IV).
- the formed suspension was stirred at 60 °C for 3 h, and cooled over a period of 3 h to 25 °C.
- the suspension was filtered on a pressure nutsch filter, and the filter cake was washed twice with a mixture of isopropanol (170 L), ethyl acetate (78 kg) and water (17 L).
- the filter cake was broken up and dried on trays in a vacuum oven at 60 °C for 5 days to yield Compound (V) (163 kg, 94%) as an off-white solid.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
- Catalysts (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Priority Applications (12)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020177015206A KR20170093821A (ko) | 2014-12-12 | 2015-12-10 | 이달로피르딘의 제조 방법 |
JP2017531139A JP2017537128A (ja) | 2014-12-12 | 2015-12-10 | イダロピルジンの製造の方法 |
CA2968770A CA2968770A1 (fr) | 2014-12-12 | 2015-12-10 | Procede de fabrication d'idalopirdine |
EP15821029.4A EP3230265A1 (fr) | 2014-12-12 | 2015-12-10 | Procédé de fabrication d'idalopirdine |
SG11201704523WA SG11201704523WA (en) | 2014-12-12 | 2015-12-10 | A process for the manufacture of idalopirdine |
BR112017012021A BR112017012021A2 (pt) | 2014-12-12 | 2015-12-10 | um processo para a fabricação de idalopirdina |
MX2017007510A MX2017007510A (es) | 2014-12-12 | 2015-12-10 | Un proceso para la fabricacion de idalopirdina. |
CN201580065028.6A CN107001266A (zh) | 2014-12-12 | 2015-12-10 | 用于生产艾达鲁吡啶的方法 |
AU2015359347A AU2015359347A1 (en) | 2014-12-12 | 2015-12-10 | A process for the manufacture of idalopirdine |
RU2017120216A RU2017120216A (ru) | 2014-12-12 | 2015-12-10 | Способ производства идалопирдина |
IL252471A IL252471A0 (en) | 2014-12-12 | 2017-05-23 | A process for the production of idalopyridine |
CONC2017/0005357A CO2017005357A2 (es) | 2014-12-12 | 2017-05-26 | Un proceso para la fabricación de idalopirdina |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DKPA201400721 | 2014-12-12 | ||
DK201400721 | 2014-12-12 |
Publications (1)
Publication Number | Publication Date |
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WO2016091997A1 true WO2016091997A1 (fr) | 2016-06-16 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2015/079209 WO2016091997A1 (fr) | 2014-12-12 | 2015-12-10 | Procédé de fabrication d'idalopirdine |
Country Status (5)
Country | Link |
---|---|
US (1) | US20160168089A1 (fr) |
AR (1) | AR102980A1 (fr) |
SG (1) | SG11201704523WA (fr) |
TW (1) | TW201630881A (fr) |
WO (1) | WO2016091997A1 (fr) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017174691A1 (fr) | 2016-04-08 | 2017-10-12 | H. Lundbeck A/S | Procédé de fabrication d'idalopirdine par hydrogénation d'une imine |
WO2018013686A1 (fr) * | 2016-07-12 | 2018-01-18 | Concert Pharmaceuticals, Inc. | Idalopirdine deutérée |
US10196363B2 (en) | 2014-12-12 | 2019-02-05 | Japan Tobacco Inc. | Dihydropyrimidin-2-one compounds and medical use thereof |
US10899717B2 (en) | 2018-02-28 | 2021-01-26 | Japan Tobacco Inc. | 4-methyldihydropyrimidinone compounds and pharmaceutical use thereof |
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JP5373764B2 (ja) * | 2007-04-16 | 2013-12-18 | マリンクロッド エルエルシー | 触媒性水素転移反応を使用する新規なオピエート還元 |
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- 2015-12-10 US US14/965,308 patent/US20160168089A1/en not_active Abandoned
- 2015-12-10 WO PCT/EP2015/079209 patent/WO2016091997A1/fr active Application Filing
- 2015-12-10 SG SG11201704523WA patent/SG11201704523WA/en unknown
- 2015-12-11 AR ARP150104048A patent/AR102980A1/es unknown
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10196363B2 (en) | 2014-12-12 | 2019-02-05 | Japan Tobacco Inc. | Dihydropyrimidin-2-one compounds and medical use thereof |
WO2017174691A1 (fr) | 2016-04-08 | 2017-10-12 | H. Lundbeck A/S | Procédé de fabrication d'idalopirdine par hydrogénation d'une imine |
US9975850B2 (en) | 2016-04-08 | 2018-05-22 | H. Lundbeck A/S | Process for the manufacture of idalopirdine via hydrogenation of an imine |
WO2018013686A1 (fr) * | 2016-07-12 | 2018-01-18 | Concert Pharmaceuticals, Inc. | Idalopirdine deutérée |
US10899717B2 (en) | 2018-02-28 | 2021-01-26 | Japan Tobacco Inc. | 4-methyldihydropyrimidinone compounds and pharmaceutical use thereof |
Also Published As
Publication number | Publication date |
---|---|
US20160168089A1 (en) | 2016-06-16 |
AR102980A1 (es) | 2017-04-05 |
TW201630881A (zh) | 2016-09-01 |
SG11201704523WA (en) | 2017-07-28 |
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